Endophenotypes of Juvenile Myoclonic Epilepsy

• Main Author: Shakeshaft, Amy
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2022

Juvenile Myoclonic Epilepsy (JME) is a common Idiopathic Generalised Epilepsy (IGE) with an adolescent onset and characteristic myoclonic jerks. The phenotypic spectrum of JME is broad, with some patients also experiencing absence seizures, executive function deficits and poor seizure prognosis. Alongside the hallmark generalised spike-/polyspike-and-wave epileptiform discharges observed on the EEG of patients with JME, previous studies have also shown alterations in the resting- state/interictal EEG of patients with IGE including alpha oscillatory activity and brain network topology, with evidence of these alterations also existing in unaffected relatives. Due to its complex genetic nature, results from previous genetic studies of JME have been inconsistent and therefore somewhat inconclusive. The use of endophenotypes can help to decrease the heterogeneity of complex disorders such as JME to give more statistical power in genetic association studies. In this thesis, I investigate potential neuropsychological, electrophysiological and clinical endophenotypes, or intermediate phenotypes of JME, for use in genetic association studies of the condition. These include impulsivity, as measured by the Barratt Impulsiveness Scale (BIS), resting-state EEG features and in-depth exploration of the JME clinical phenotype, including seizure type and prognostic group stratification. Participants with JME were recruited via the Biology of Juvenile Myoclonic Epilepsy (BIOJUME) study, whereby BIS-brief questionnaires, genetic, clinical and EEG data were collected. Strict eligibility criteria and a phenotyping panel confirmed a diagnosis of JME. I used multivariable, stratified analysis to explore clinical phenotypes, such as seizure types and a sensitivity to seizure precipitants, and factors influencing prognosis in 765 individuals with JME. Further, I compared JME BIS-brief scores (n=322) to matched controls and other clinical cohorts from the literature and explored clinical associations of impulsivity in JME. A comparison of resting-state EEG features, such as power spectral density, network topology and a dynamic measure of network ictogenicity (Brain Network Ictogenicity), between JME (n=147) and control EEGs (n=95) was carried out to assess their use as biomarkers and endophenotypes. Finally, a genome-wide association study (GWAS) and hypothesis-driven candidate gene study of three endophenotypes (trait impulsivity, measured by the BIS-brief, and two resting- state EEG features) in JME was carried out in collaboration with members of the BIOJUME consortium. Regarding the clinical phenotype of JME, I observed that poor seizure prognosis is associated with experiencing absence seizures in both males and females, while a susceptibility to stress-related precipitants negatively modifies disease course in females only. Alongside the association with poor seizure control, absence seizures are also associated with increased trait impulsivity which is significantly higher in JME than in matched controls, to a level equivalent to cohorts with neurotic- type disorders. GWAS analysis of trait impulsivity in 373 individuals with JME gave 3 significantly associated loci, annotated to SLCO5A1, DUSP10 and PARD3 genes, exemplifying the strength of using endophenotypes to uncover novel genetic associations. In addition, gene-set enrichment analysis indicated an 8.5-fold enrichment of genes involved in the regulation of presynapse assembly/organisation in the GWAS of trait impulsivity. Analysis of resting-state EEG features showed significant differences between JME and control EEGs, particularly features relating to activity in the low-alpha frequency range (6-9Hz) and network ictogenicity, whilst network topology measures showed significant associations with JME clinical characteristics and outcomes. Genetic association analysis of two EEG endophenotypes (Brain Network Ictogenicity (BNI) and low-alpha power spectral density) with associated genes in the impulsivity GWAS (SLCO5A1, DUSP10 and PARD3) and genes involved in the regulation of presynapse assembly/organisation (n=33 genes), showed an association of SNPs at the PTPRD locus (a gene involved in the regulation of presynapse organisation/assembly) with BNI. Overall, this thesis verifies the heterogeneity of clinical, electrophysiological and neuropsychological phenotypes of JME and supports the use of endophenotypes to increase the power to detect novel and significant genetic associations in complex diseases. In addition, results from genetic association analyses suggest further research into presynapse organisation/assembly in the pathophysiology of JME.